VNN1 promotes atherosclerosis progression in apoE-/- mice fed a high-fat/high-cholesterol diet.
VNN1 promotes atherosclerosis progression in apoE-/- mice fed a high-fat/high-cholesterol diet.
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VNN1 促进高脂肪/高胆固醇饮食的 apoE(-/-) 小鼠动脉粥样硬化进展
DOI：
10.1194/jlr.m065565
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发表时间：
2016-08
影响因子：
6.5
通讯作者：
Wang Q
中科院分区：
文献类型：
--
作者：
Hu YW;Wu SG;Zhao JJ;Ma X;Lu JB;Xiu JC;Zhang Y;Huang C;Qiu YR;Sha YH;Gao JJ;Wang YC;Li SF;Zhao JY;Zheng L;Wang Q
越来越多的证据表明vanin-1（VNN 1）在葡萄糖代谢中起着关键作用。我们探索了VNN 1对胆固醇代谢、炎症、体外细胞凋亡和apoE−/−小鼠动脉粥样硬化斑块进展的影响。氧化型低密度脂蛋白（Ox-LDL）通过ERK 1/2/环氧合酶-2/过氧化物酶体增殖物激活受体α（PPARα）信号通路诱导VNN 1表达。VNN 1可显著增加THP-1巨噬细胞源性泡沫细胞胆固醇含量，使apoAI和HDL-C介导的外排率分别降低25.16%和23.13%（P < 0.05）。VNN 1通过上调THP-1巨噬细胞p53蛋白表达59.15%，下调B细胞淋巴瘤-2蛋白表达127.13%，抑制Ox-LDL诱导的THP-1巨噬细胞凋亡（P < 0.05）。在体内，apoE−/−小鼠被随机分为两组，并用慢病毒（LV）-Mock或LV-VNN 1转导12周。VNN 1组小鼠肝脏脂质含量和血浆TG（124.48%）、LDL-胆固醇（119.64%）、TNF-α（148.74%）、IL-1 β（131.81%）、IL-6（156.51%）水平显著升高，而血浆HDL-C（25.75%）水平显著降低（P < 0.05）。与这些数据相一致的是，在用LV-VNN 1感染apoE−/−小鼠后，动脉粥样硬化病变的发展显著增加。这些观察结果表明，VNN 1可能是一个有前途的治疗候选人对动脉粥样硬化。
Accumulated evidence shows that vanin-1 (VNN1) plays a key part in glucose metabolism. We explored the effect of VNN1 on cholesterol metabolism, inflammation, apoptosis in vitro, and progression of atherosclerotic plaques in apoE−/− mice. Oxidized LDL (Ox-LDL) significantly induced VNN1 expression through an ERK1/2/cyclooxygenase-2/PPARα signaling pathway. VNN1 significantly increased cellular cholesterol content and decreased apoAI and HDL-cholesterol (HDL-C)-mediated efflux by 25.16% and 23.13%, respectively, in THP-1 macrophage-derived foam cells (P < 0.05). In addition, VNN1 attenuated Ox-LDL-induced apoptosis through upregulation of expression of p53 by 59.15% and downregulation of expression of B-cell lymphoma-2 127.13% in THP-1 macrophage (P < 0.05). In vivo, apoE−/− mice were divided randomly into two groups and transduced with lentivirus (LV)-Mock or LV-VNN1 for 12 weeks. VNN1-treated mice showed increased liver lipid content and plasma levels of TG (124.48%), LDL-cholesterol (119.64%), TNF-α (148.74%), interleukin (IL)-1β (131.81%), and IL-6 (156.51%), whereas plasma levels of HDL-C (25.75%) were decreased significantly (P < 0.05). Consistent with these data, development of atherosclerotic lesions was increased significantly upon infection of apoE−/− mice with LV-VNN1. These observations suggest that VNN1 may be a promising therapeutic candidate against atherosclerosis.